Despite procedural success rates greater than 95% achieved by percutaneous transluminal coronary angioplasty (PTCA), luminal renarrowing of blood vessels after balloon angioplasty occurs in 30% to 60% of all cases within 3 to 6 months. Smooth muscle cell proliferation and extracellular matrix remodeling appear to play pivotal roles in the luminal renarrowing process and negate the beneficial effect of vascular reconstruction by angioplasty (Leclercq et al., Arch. Mal. Coeur. Vaiss. 89:359-365 (1996)). The use of new technology, such as atherectomy, excimer laser, stent or rotablator (Hofling et al., Z. Kardiol. 80:25-34 (1991); Margolis et al., Clin. Cardiol. 14:489-493 (1991); Serruys et al., J. Am Coll. Cardiol. 17:143B-154B (1991); Warth et al., J. Am. Coll. Cardiol. 34:641-648 (1994)) has not been able to reduce the incidence of restenosis significantly.
A variety of drugs also have been investigated to prevent luminal renarrowing in experimental animal and clinical settings, but without much success. A primary reason for this may be the failure of systemic administration to achieve effective concentrations of drugs at the targeted area. To overcome this deficiency, new endoluminal catheter delivery systems with various balloon configurations have been employed for localizing drug delivery. These include: hydrogel balloon, laser-perforated (Wolinsky balloon), ‘weeping,’ channel and ‘Dispatch’ balloons and variations thereof (Azrin et al., Circulation 90:433 (1994); Consigny et al., J. Vasc. Interv. Radiol 5:553 (1994); Wolinsky et al., JACC, 17:174B (1991); Riessen et al., JACC 23:1234 (1994); Schwartz, Restenosis Summit VII, Cleveland, Ohio, 1995, pp 290-294). Delivery capacity with hydrogel balloon is limited and, during placement, the catheter can lose substantial amount of the drug or agent that is administered. High pressure jet effect in Wolinsky balloon can cause vessel injury which can be avoided by making many holes, <1 μm, (weeping type). The ‘Dispatch’ catheter has generated a great deal of interest for drug delivery as it creates circular channels and can be used as a perfusion device, allowing continuous blood flow. However, each of these devices have limitations and have not been successful in resolving the problem of restenosis.
The cell membrane may be transiently permeabilized by subjecting cells to a brief, high intensity, electric field. This pulse-induced permeabilization of cell membranes, termed electroporation, has been used by investigators to introduce various compositions such as DNA, RNA, proteins, liposomes, latex beads, whole virus particles and other macromolecules into living cells (Hapala, Crit. Rev. Biotechnol. 17:105-122 (1997)). In particular, for example, large size nucleotide sequences (up to 630 Kb) can be introduced into mammalian cells via electroporation (Eanault et al., Gene 144:205 (1994); Nucl. Acids Res. 15:1311 (1987); Knutson et al., Anal. Biochem. 164:44 (1987); Gibson et al., EMBO J. 6:2457 (1987); Dower et al., Genetic Engineering 12:275 (1990); Mozo et al., Plant Molecular Biology 16:917 (1991)). These studies show that electroporation affords an efficient means to deliver therapeutic compositions such as drugs, genes, polypeptides and the like in vivo by applying an electrical pulse to particular cells or tissues within a subject.
Several therapeutic applications of electroporation are now being explored: treatment of restenosis using angioplasty combined with electroporation to deliver drugs to a localized portion of coronary or peripheral arteries (Shapland et al., U.S. Pat. No. 5,498,238); treatment of cancer by electroporation in the presence of low doses of chemotherapeutic drugs (Mir, U.S. Pat. No. 5,468,223); introduction of functional genes for gene therapy (Nishi et al., Cancer Research 56:1050-1055 (1996)), electroporation of skin for the delivery of drugs into the skin or for the transdermal delivery of drugs across tissue (Zhang et al., Biochem. Biophys. Res. Comm. 220:633-636 (1996)); Weaver et al., U.S. Pat. No. 5,019,034; Prausnitz, Adv. Drug. Deliv. 18:395-425 (1996)). Hofmann describes a syringe apparatus for electroporating molecules and macromolecules into tissue regions in vivo in which the needles of the syringe used to deliver the molecules also function as electrodes (U.S. Pat. No. 5,273,525). Weaver describes an apparatus for the delivery of chemical agents into tissues in vivo via electroporation (U.S. Pat. No. 5,389,069). Hofmann et al., describe methods for delivering genes or drugs via electroporation to treat endothelial and other cells of blood vessels, for example, and an electroporation catheter device that can be used to practice the methods (U.S. Pat. No. 5,507,724). Crandell et al. describe the use of a catheter apparatus for introducing therapeutic macromolecules via electroporation into endothelial cells of a patients' blood vessels (U.S. Pat. No. 5,304,120).
However, in view of the limited success in preventing luminal renarrowing after angioplasty, a need exists for the development of methods for inducing or increasing vessel vasodilation in order to treat undesirable vessel narrowing without therapeutic compositions, many of which elicit adverse side effects. The present invention satisfies this need and provides related advantages as well.